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Science. 2011 Apr 29;332(6029):600-3. doi: 10.1126/science.1202947. Epub 2011 Apr 7.

Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.

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  • 1Medical Research Council (MRC) Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham B15 2TT, UK.

Abstract

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.

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PMID:
21474713
PMCID:
PMC3198051
DOI:
10.1126/science.1202947
[PubMed - indexed for MEDLINE]
Free PMC Article

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